WBR0250
| Author | [[PageAuthor::Yazan Daaboul, M.D. (Reviewed by Yazan Daaboul, M.D.)]] |
|---|---|
| Exam Type | ExamType::USMLE Step 1 |
| Main Category | MainCategory::Genetics |
| Sub Category | SubCategory::Dermatology, SubCategory::Oncology |
| Prompt | [[Prompt::A 42-year-old fair-skinned man presents to the dermatology clinic for a rapidly growing nevus on his back. The patient reports that the lesion has recently been increasing in size and has been getting progressively darker over the past few months. Evaluation of the lesion reveals a 9 cm x 4 cm asymmetrical nevus with irregular border and heterogeneous dark color. Excisional biopsy of the lesion reveals extensive proliferation of melanocytes, intraepidermal growth, and cellular atypia. Mutation of which gene is associated with the development of this patient's condition?]] |
| Answer A | AnswerA::''APC'' |
| Answer A Explanation | [[AnswerAExp::Loss-of-function of the APC gene is associated with development familial forms of colorectal cancer.]] |
| Answer B | AnswerB::''WT1'' |
| Answer B Explanation | [[AnswerBExp::Loss-of-function of the gene WT1 is associated with development of Wilms tumor.]] |
| Answer C | AnswerC::''DPC'' |
| Answer C Explanation | [[AnswerCExp::Loss-of-function of DPC gene (Deleted in Pancreatic Cancer gene) is associated with development of pancreatic cancer.]] |
| Answer D | AnswerD::''BRAF'' |
| Answer D Explanation | AnswerDExp::Activating mutation of the ''BRAF'' gene, a member of the ''RAF'' gene family, is present among the majority of patients with melanoma. |
| Answer E | AnswerE::''RB'' |
| Answer E Explanation | [[AnswerEExp::Loss-of-function of the RB gene is associated with development of retinoblastoma and osteosarcoma.]] |
| Right Answer | RightAnswer::D |
| Explanation | [[Explanation::Malignant melanoma is the most common fatal skin cancer that arises from the epidermal melanocytes, which are neural crest cells that migrate to the skin during embryogenesis. Normally, melanocytes play a role in the synthesis of melanin, a brown pigment with photoprotective properties. Important risk factors that contribute to the development of melanoma include genetic mutations, chronic ultraviolet exposure, high frequency of sunburns, fair skin color, and freckles. Germline mutations that predispose to melanoma include mutations in the CDKN2A tumor suppressor gene that encodes p16 and p19 and cause familial melanoma. Most importantly, activating BRAF mutations in chromosome 7 are present in the majority of patients with non-familial melanoma, especially among those with no chronic sun exposure. B-Raf protein is a serine/threonine kinase that activates MAP kinase/ERK signaling pathway. The most common BRAF mutation in melanoma is the BRAFV600E mutation, which is characterized by the substitution of glutamic acid for valine in BRAF gene at codon 600.
Melanoma typically manifests as a growing, asymmetric nevus with irregular borders, and heterogeneous discoloration, as described in the vignette. The ABCDE of melanoma are important clues on history and physical examination: Asymmetry, Border irregularity, Color changes, Diameter > 6 - 8 mm, and Evolution over time. The diagnosis of melanoma requires excisional biopsy, which may show proliferation of melanocytes, dysplastic cells and atypia. If left untreated, melanocytes first proliferate randomly with an aberrant growth within an existing nevus. More advanced stages are characterized by a radial-growth phase with intraepidermal growth and penetration into the papillary dermis. Final stages demonstrate a vertical-growth phase with dermal invasion and widening of the papillary dermis before cancerous cells finally metastasize to other parts of the skin and other organs. Management of melanoma includes wide excision of the lesion for all patients and administration of BRAF kinase inhibitors, such as sorafenib (non-selective) or vemurafenib (selective), for patients with BRAF mutations. |
| Approved | Approved::Yes |
| Keyword | WBRKeyword::Melanoma, WBRKeyword::BRAF, WBRKeyword::B-RAF, WBRKeyword::RAF, WBRKeyword::Mutation, WBRKeyword::Malignant melanoma, WBRKeyword::Skin cancer, WBRKeyword::Vemurafenib, WBRKeyword::Sorafenib, WBRKeyword::Protein kinase, WBRKeyword::Kinase, WBRKeyword::MAP kinase, WBRKeyword::Nevus |
| Linked Question | Linked:: |
| Order in Linked Questions | LinkedOrder:: |